10.3389/fmolb.2019.00095.s001
Havva Yalinca
Havva
Yalinca
Charlotte Julie Caroline Gehin
Charlotte Julie Caroline
Gehin
Vladimiras Oleinikovas
Vladimiras
Oleinikovas
Hilal A. Lashuel
Hilal A.
Lashuel
Francesco Luigi Gervasio
Francesco Luigi
Gervasio
Annalisa Pastore
Annalisa
Pastore
Presentation_1_The Role of Post-translational Modifications on the Energy Landscape of Huntingtin N-Terminus.pdf
Frontiers
2019
Huntington's disease
misfolding disease
molecular dynamics
peptide folding
phosphorylation
post-translational modifications
enhanced sampling
2019-10-01 04:03:16
Presentation
https://frontiersin.figshare.com/articles/presentation/Presentation_1_The_Role_of_Post-translational_Modifications_on_the_Energy_Landscape_of_Huntingtin_N-Terminus_pdf/9922796
<p>Huntington disease is a neurodegenerative disease characterized by a polymorphic tract of polyglutamine repeats in exon 1 of the huntingtin protein, which is thought to be responsible for protein aggregation and neuronal death. The polyglutamine tract is preceded by a 17-residue sequence that is intrinsically disordered. This region is subject to phosphorylation, acetylation and other post-translational modifications in vivo, which modulate its secondary structure, aggregation and, subcellular localization. We used Molecular Dynamics simulations with a novel Hamiltonian-replica-exchange-based enhanced sampling method, SWISH, and an optimal combination of water and protein force fields to study the effects of phosphorylation and acetylation as well as cross-talk between these modifications on the huntingtin N-terminus. The simulations, validated by circular dichroism, were used to formulate a mechanism by which the modifications influence helical conformations. Our findings have implications for understanding the structural basis underlying the effect of PTMs in the aggregation and cellular properties of huntingtin.</p>